The primary objective of the study is to demonstrate the reduction of LDL-C by REGN727 as add-on therapy to stable, maximally-tolerated dialy statin therapy with or without other LMT in comparison with placebo after 24 weeks of treatment in patients…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
- Lipid metabolism disorders
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The percent change in calculated LDL-C from baseline to week 24, which is
defined as : 100x (calculated LDL-C value at week 24 - calculated LDL-C value
at baseline) / calculated LDL-C value at baseline.
The baseline calculated LDL-C value will be the last LDL-C level obtained
before the first double-blind IMP injection.
Secondary outcome
The percent change in calculated LDL-C from baseline to week 12.
The percent change in calculated Apo B from baseline to week 24
The percent change in calculated non-HDL-C from baseline to week 24
The percent change in calculated total-C from baseline to week 24
The percent change in calculated Apo B from baseline to week 12
The percent change in calculated non-HDL-c from baseline to week 12
The percent change in calculated total-C from baseline to week 12
The percent change in calculated LDL-C from baseline to week 52
The proportion of patients reaching LDL-C goal at week 24, i.e. LDL-C < 70
mg/dL in case of prior cardiovascular disease, or LDL-C < 100 mg/dL for
patients without cardiovascular disease.
The proportion of patients reaching LDL-C < 70 mg/dL (1.81 mmol/L) at week 24
The percent change in Lp(a) from baseline to week 24
The percent change in HDL-C from baseline to week 24
The percent change in Lp(a) from baseline to week 12
The percent change in fasting TG from baseline to week 24
The percent change in fasting TG from baseline to week 12
The percent change in Apo A-1 from baseline to week 24
The percent change in Apo A-1 from baseline to week 12
The percent change in HDL-C from baseline to week 12
The percent change in calculated LDL-C from baseline to week 78
The proportion of patients reaching LDL-C goal at week 12, 52, and 78, i.e.
LDL-C < 70 mg/dL in case of prior cardiovascular disease, or LDL-C < 100 mg/dL
for patients without cardiovascular disease.
The proportion of patients reaching LDL-C < 100 mg/dL (2.59 mmol/L) at week 24
The proportion of patients reaching LDL-C < 100 mg/dL (2.59 mmol/L) at week 12
The proportion of patients reaching LDL-C < 70 mg/dL (1.81 mmol/L) at week 12
The absolute change in calculated LDL-C (mg/dL and mmol/L) from baseline to
Weeks 12, 24, 52 and 78
The percent change in Apo B, non-HDL-C, total-C, Lp (a), HDL-C, fasting TG, and
Apo A-1 from baseline to Week 52 and 78
The change in ratio Apo B / Apo A-1 from baseline to weeks 12, 24, 52 and 78
The proportion of patients with Apo B < 80 mg/dL (0.8 mmol/L) at weeks 12, 24,
52 and 78
The proportion of patients with non-HCL-C < 100 mg/dL at weeks 12, 24, 52 and
78.
The proportion of patients with calculated LDL-C < 70 mg/dL (1.81 mmol/L)
and/or > or equal to 50*% reduction in calculated LDL-C (if calculated LDL-C >
or equal to 70 mg/dL (1.81 mmol/L) ) at weeks 12, 24, 52 and 78.
Anti-REGN727 antibody status and titers assessed throughout the study
The percent change in hs-CRP from baseline to weeks 24, 52 and 78
The absolute change in HbA1c (%) from baseline to weeks 24, 52 and 78
Response of each EQ-5D item, index score and change of index score from
baseline through week 52
Background summary
The study will include patients with heterozygous familial
hypercholesterolemia (heFH) with or without a history of MI or ischemic stroke.
Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism
that predisposes a person to premature severe cardiovascular disease (CVD).
Familial hypercholesterolemia has a high prevalence in Caucasian populations,
were estimated 1 in 500 individuals are affected.
In the heterozygous form of FH, the cumulative risk of experiencing a coronary
event by the age of 60 years without effective treament is at least 50% in men
and approximately 30% in women.
In 4 observational studies, statin therapy was shown to reduce the risk of CVD
by 50% to 80% in patients with FH. Unfortunately, even after treatment, the
risk in heFH can still be almost 2-fold higher than the general population. In
addition only a small fraction of treated heFH patients are able to reach
recommended levels of LDL-C. Thus, the need for more intensive treatment in
heFH patients is clear.
REGN727 is a fully human monoclonal antibody that binds Propotein Convertase
Subtilisin Kexin type 9 (PCSK9).
PCSK9 which is highly expressed in the liver, is involved in regulating the
levels of Low-density lipoportein receptor (LDL-R) protein. Once secreted into
plasma, PCSK9 binds to the LDL-R and promotes its degeneration, which leads to
reduced LDL-C removal or higher LDL-C circulating levels.
Therefor blocking PCSK9 can potentially benefit patients by decreasing their
plasma LDL-C levels. In addition, PCSK9 messenger ribonucleic acid (mRNA) and
protein levels are increased in response to statins, potentially attenuating
their cholesterol-lowering effect.
Study objective
The primary objective of the study is to demonstrate the reduction of LDL-C by
REGN727 as add-on therapy to stable, maximally-tolerated dialy statin therapy
with or without other LMT in comparison with placebo after 24 weeks of
treatment in patients with heFH.
Study design
This is a randomized, double-blind, placebo-controlled, parallel-group,
multi-national study in patients with heFH who are not adequatley controlled
with their LMT.
Pateints will be randomized in a 2:1 ratio to receive either 75 mg REGN727 or
placebo by SC injection, every 2 weeks, on top of stable, maximally-tolerated
dialy statin therapy with or without other LMT. Randomization will be
stratified according to prior history of either myocardial infarction or
ischemic stroke, and statin treatment
The study consists of :
1) A screening period of up to 2 weeks
2) A double-blind treatment period of 78 weeks, after completion of this
period, patients may bbe eligible to enroll into a separate open-label
extention study.
3) A follow-up period of 8 weeks
Intervention
Biweekly subcutaneous injections with 75mg/ml study drug or placebo.
At week 12, patients randomized to REGN727 will, in a blinded manner, dose
up-titrate to REGN727 150mg every 2 weeks, if the week 8 LDL-C is higher or
equal to 70 mg/dl (1.8 mmol/L).
Study burden and risks
This study consists of 3 periods:
1)screening period up to 2 weeks including an intermediate visit during which
the patient will be trained to self-inject of the study medication.
2)Double-blind treatment period of 18 months with 10 visits. During each visit
there will be a fasting bloodsampling, there will be 5 urine sampling except
for the women of childbearing potential, they will give more urine samples (7)
for pregnancy testing. During each visit bloodpressure and heartrate will be
monitored . During the complete treatment period the patient will receive three
ECG and six questionnaires. Between the visits the patient will keep a diary
and follow a diet to decrease the cholesterol.
3) Follow-up period of 8 weeks after the end of the previous period for
patients not consenting to participate in the open-label extension study or if
prematurely discontinuing study treatment
REGN727 was well tolerated in all completed Phase 2 studies throughout the
treatmentperiod and for all treatment groups. Injection site reactions were
reported in patients including placebo-treated patients. These events were
generally transient with no dose relationship. Rare cases of hypersensitivity
reactions were reported. . No particular signal noted for "treament emergent
adverse events" related to musculoskeletal or connective tissue disorders as
well as no elevations in liver enzymes.
As with any experimental drug, there may be side effects that are unknown and
that could occur when the drug is taken alone or in combination with other
drugs.
The effect of REGN727 on pregnancy or breast feeding mothers is not known at
this time.
Old Saw Mill River Road 777
Tarrytown 10591 NY
US
Old Saw Mill River Road 777
Tarrytown 10591 NY
US
Listed location countries
Age
Inclusion criteria
1.Patients with heFH* who are not adequately controlled** with a maximally-tolerated daily dose*** of statin with or without other LMT, at a stable dose prior to the screening visit (week -2).;*Diagnosis of heFH must be made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may be based on either the Simon Broome criteria for definite FH (Appendix 1) or the WHO/Dutch Lipid Network criteria with a score of >8 points (Appendix 2).;***Not adequately controlled* is defined as LDL-C *70 mg/dL (1.81 mmol/L) at the screening visit (week -2) in patients with a history of documented CVD (Appendix 3), or LDL-C *100 mg/dL (2.59 mmol/L) at the screening visit (week -2) in patients without a history of documented CVD.;****Maximally-tolerated dose* is defined as (any of the following are acceptable):;*Rosuvastatin 20 mg or 40 mg daily;*Atorvastatin 40 mg or 80 mg daily;*Simvastatin 80 mg daily (if already on this dose for >1 year * see exclusion criterion #7);Note: Patients who are not able to be on any of the above statin doses should be treated with the dose of daily atorvastatin, rosuvastatin, or simvastatin which is considered appropriate for the patient, according to the investigator's judgment. Some examples of acceptable reasons for a patient taking a lower statin dose include, but are not limited to: adverse effects on higher doses, advanced age, low body mass index, regional practices, local prescribing information, concomitant medications, co-morbid conditions such as impaired glucose tolerance/impaired fasting glucose. The reason(s) will be documented in the case report form (CRF).;2.Provide signed informed consent
Exclusion criteria
1.Patient without diagnosis of heFH made either by genotyping or by clinical criteria;2.LDL-C <70 mg/dL (<1.81 mmol/L) at the screening visit (week-2) in patients with history of documented cardiovascular disease;3.LDL-C <100 mg/dL (<2.59 mmol/L) at the screening visit (week *2) in patients without history of documented cardiovascular disease;4.Not on a stable dose of LMT (including statin) for at least 4 weeks and/or fenofibrate for at least 6 weeks, as applicable, prior to the screening visit (week -2) and from screening to randomization;5.Currently taking another statin than simvastatin, atorvastatin, or rosuvastatin;6.Simvastatin, atorvastatin, or rosuvastatin is not taken daily or not taken at a registered dose;7.Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg (except for patients on simvastatin 80 mg for more than 1 year, who are eligible);8.Use of fibrates, other than fenofibrate within 6 weeks of the screening visit (week-2) or between screening and randomization visits;9.Use of nutraceutical products or over-the-counter therapies that may affect lipids which have not been at a stable dose/amount for at least 4 weeks prior to the screening visit (week -2) or between screening and randomization visits;10.Use of red yeast rice products within 4 weeks of the screening visit (week-2), or between screening and randomization visits;11.Patient who has received plasmapheresis treatment within 2 months prior to the screening visit (week -2), or has plans to receive it during the study;12.Recent (within 3 months prior to the screening visit [week -2] or between screening and randomization visits) MI, unstable angina leading to hospitalization, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), uncontrolled cardiac arrhythmia, stroke, transient ischemic attack (TIA), carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-001222-95-NL |
| CCMO | NL41314.018.12 |